Puerarin Attenuates Osteoarthritis via Multi‐Target Regulation of Inflammation, Apoptosis, and ECM Degradation

ABSTRACT Osteoarthritis (OA) is a degenerative joint disease characterised by cartilage breakdown, leading to pain and reduced quality of life. This study aims to investigate the therapeutic potential of Puerarin (PUE), a natural compound derived from Pueraria lobata , in modulating OA progression. Employing a multifaceted approach that included bioinformatics analysis, molecular docking, in vitro assays, and in vivo experiments, we identified 57 overlapping targets between PUE and OA‐related genes, suggesting a multi‐target interaction model. Our findings revealed that PUE effectively inhibited inflammatory cytokine production and protected chondrocytes from apoptosis at non‐cytotoxic concentrations (5 and 10 μM), promoting extracellular matrix synthesis by reversing IL‐1β‐induced degradation of Aggrecan and Collagen II while reducing MMP‐13 and ADAMTS5 expression. Furthermore, PUE was shown to attenuate IL‐1β‐induced apoptosis by restoring BCL‐2 levels and decreasing cleaved caspase‐3 levels. In vivo, PUE administration in a destabilisation of the medial meniscus (DMM) mouse model significantly slowed OA progression, preserving cartilage structure and reducing osteophyte formation. Moreover, PUE activated the PI3K‐AKT signalling pathway, underscoring its anti‐inflammatory and anti‐apoptotic mechanisms. Collectively, these results support Puerarin's potential as a disease‐modifying agent in OA treatment, warranting further clinical exploration and consideration of its application in combination therapies to enhance cartilage protection and repair.